Molecular windows into the human brain for psychiatric disorders

Abstract

Delineating the pathophysiology of psychiatric disorders has been extremely challenging but technological advances in recent decades have facilitated a deeper interrogation of molecular processes in the human brain. Initial candidate gene expression studies of the postmortem brain have evolved into genome wide profiling of the transcriptome and the epigenome, a critical regulator of gene expression. Here, we review the potential and challenges of direct molecular characterization of the postmortem human brain, and provide a brief overview of recent transcriptional and epigenetic studies with respect to neuropsychiatric disorders. Such information can now be leveraged and integrated with the growing number of genome-wide association databases to provide a functional context of trait-associated genetic variants linked to psychiatric illnesses and related phenotypes. While it is clear that the field is still developing and challenges remain to be surmounted, these recent advances nevertheless hold tremendous promise for delineating the neurobiological underpinnings of mental diseases and accelerating the development of novel medication strategies.

Figure 1. Molecular phenotyping of the post-mortem human brain has progressed along with technological advancements

Gene expression that initially was assessed in a low-throughput and hypothesis-driven manner using qPCR or in situ hybridization histochemistry for individual genes, can now be profiled genome-wide employing microarray or RNA-sequencing technologies. The epigenetic landscape (comprised of DNA methylation and hydroxymethylation, histone post-translational modifications, nucleosome positioning, microRNAs, and long non-coding RNAs as well as hierarchical 3D structures of the chromatin) mediates the effects of environmental influences on gene expression during development and throughout adult life. Epigenetic modifications mark non-coding regulatory elements (such as promoters and enhancers) and can now be assessed using multiple whole-genome strategies, including DNA bisulfite sequencing, ChIP-seq and ATAC-seq. These datasets can then be integrated with GWAS findings to infer the functional significance of risk variants. Lastly, due to extreme cellular heterogeneity of the brain and because many epigenetic marks differ between the cell types, an important future direction is to obtain transcriptional and epigenetic profiling of different cell populations and single cells, which are now feasible to carry out with postmortem human brain specimens.

Figure 2. OPRM1 and OPRD1 expression (RNA-seq, Left) and H3K27ac enrichment profiles (ChIP-seq, Right) in GABA and Glu nuclei from human PFC

Left, RNA-seq data from 10 individuals are analyzed. Right, H3K27ac data are shown for 3 individuals. Two SNPs (red triangles) implicated in opioid addiction are situated within cell-type specific H3K27ac peaks. For each of the two genes, the signals are presented in the same scale across cell types and biological replicates.